Sodium Carbonate → Ethyl 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-5-methylbiphenyl-4-yl)acetate

HRID 1930113Notes

Reaction equation

HRID 1930113 reaction equation
[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2].[Cl:21][C:22]1[C:23](OS(C(F)(F)F)(=O)=O)=[CH:24][C:25]([CH3:34])=[C:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>COCCOC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:23]3[CH:24]=[C:25]([CH3:34])[C:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][C:22]=3[Cl:21])=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2]

Participants

8

Reactant 4

HCID 10340Sodium Carbonate2×HCID 433294Lithium ChlorideHCID 59627724Ethyl 2-(5-chloro-2-methyl-4-(trifluoromethylsulfonyloxy)phenyl)acetate2×HCID 596277414-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid2×

Product 1

HCID 59627700Ethyl 2-(4'-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-5-methylbiphenyl-4-yl)acetateYield 70.7%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalyst2×HCID 702EthanolSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid (Intermediate 5-1; 284 mg, 1.05 mmol) and ethyl 2-(5-chloro-2-methyl-4-(trifluoromethylsulfonyloxy)phenyl)acetate (Intermediate 3-2; 336 mg, 0.93 mmol) and 2M sodium carbonate (0.757 mL, 1.51 mmol), tetrakis(triphenylphosphine)palladium(0) (66.7 mg, 0.06 mmol) and lithium chloride (69.1 mg, 1.63 mmol) in DME (20 mL) and ethanol (5 mL) was degassed and then stirred at 85° C. After 4 hours further tetrakis(triphenylphosphine)palladium(0) (100 mg) and 2M sodium carbonate (0.5 mL) were added and heating was continued for a further 17 hours (overnight). The reaction mixture was allowed to cool, evaporated and partitioned between EtOAc (100 mL), water (50 mL) and 2M HCl (10 mL). The aqueous phase was re-extracted with EtOAc (100 mL), the combined organic extracts were dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chloro-5-methylbiphenyl-4-yl)acetate (288 mg, 70.6%) as a yellow solid.

Workup

  1. temperatureheating
  2. custom(overnight)
  3. temperatureto cool
  4. customevaporated
  5. custompartitioned between EtOAc (100 mL), water (50 mL) and 2M HCl (10 mL)
  6. extractionThe aqueous phase was re-extracted with EtOAc (100 mL)
  7. dry with materialthe combined organic extracts were dried over MgSO4
  8. filtrationfiltered
  9. customevaporated
  10. customto afford crude product
  11. customThe crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane
  12. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-ad14fd02ff00475fab54dfabecbe47d5
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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